June 17, 2005
Most Common Lung Cancers May Begin in Newly Discovered Cells
The most common form of lung cancer may begin in a group of newly
isolated lung stem cells, according to researchers from the Howard
Hughes Medical Institute.
Working in a mouse model, the researchers isolated a novel type of
lung cell that can divide into fresh copies of itself and into the two
more specialized kinds of cells deep in the lung. Their experiments
show that at the earliest stage of tumor development, the stem cell
appears to be the first lung cells that respond to a cancer-causing
mutation. The newly identified cell type fulfills all but one of the
strictest criteria that scientists look for in defining adult stem
cells.
“They may be the cells that we have to eliminate in cancer in order to obtain durable cures for the disease.”
Tyler Jacks
The study is published in the June 17, 2005, issue of the journal
Cell.
“The work of Bender Kim and colleagues represents not only a
leap forward in our understanding of lung tumorigenesis, it also
heralds the arrival of a valuable mouse model for identifying those
cells that should be the targets of therapeutic intervention,”
wrote Anton Berns of The Netherlands Cancer Center in Amsterdam in an
accompanying commentary in Cell.
The identification of the cells could lead to earlier diagnosis of
lung cancer in people. Lung cancer is the leading cause of
cancer-related death in the United States, in part because it is
usually detected at an advanced stage. Patients in whom the disease has
spread to other organs have a five-year survival rate of only two
percent. In contrast, lung cancer detected at an early stage boasts a
50 percent survival rate over a five-year period.
“There are many similarities between stem cells and
cancer,” said first author Carla Bender Kim, a postdoctoral
fellow in the lab of senior author Tyler Jacks, a Howard Hughes Medical
Institute investigator at Massachusetts Institute of Technology.
“Cancer cells can continue to divide many times. Likewise, stem
cells can divide over the lifespan of the organism. Also, tumors are
very heterogeneous, composed of many different cells, and stem cells
can give rise to different types of cells.”
The researchers do not know if the stem cells play a role in more
established tumors, but other scientists have found evidence that some
human cancers contain a small but virulent group of cells known as
“cancer stem cells” that regenerate the tumor, a capacity
that most cells in a tumor lack.
“They may be the cells that we have to eliminate in cancer in
order to obtain durable cures for the disease,” said Jacks.
“Along the way, we need to know how these cancer stem cells
become different from normal stem cells.”
Bender Kim started with a mouse model of non-small cell
adenocarcinoma recently developed by another postdoc and graduate
student in Jacks's lab to study the progression of lung cancer and the
effects of conventional and experimental therapies.
The mouse carries a silent genetic mutation of an oncogene known as
K-ras, which is found in about one-third of all tested non-small
cell lung cancers in people. A specially designed virus can activate
the mutation in only a few cells. The mouse is known as a conditional
mutant strain. In this case, the mouse inhales a small amount of virus
that activates the K-ras oncogene in some of the lung cells.
Four years ago, Jacks's lab reported that some of the resulting
cancer cells carry the molecular markers of both of the two kinds of
cells found in non-small lung cell cancers. In mice, the tumors start
deep in the lung, past the trachea and the branches to the lobes.
Ciliated cells that catch debris give way to the bronchiolar cells
called Clara cells. The airways end with the alveolar cells, which are
the grape-cluster-like sacks lined with microscopic vessels, where
oxygen and carbon dioxide are exchanged.
At the junction of the bronchioles and alveoli, other groups have
found evidence of cells that are resistant to damage and are involved
in repair and maintenance of tissue. They have proposed that these
junctions might be a stem cell niche.
Bender Kim and her co-authors first isolated the stem cells, which
they named bronchioalveolar stem cells (BASCs), from the earliest stage
of the mouse tumors. Then, she purified them from the lungs of healthy
mice. On the surface of BASCs, Bender Kim found another protein marker
that is also present on the surface of better-studied hematopoietic
stem cells. She made certain that BASCs were not stem cells of the
blood or blood vessels.
The BASCs passed the rigorous tests for stem cells. In response to
two types of lung damage that killed the more specialized cells, BASCs
proliferated and appeared to give rise to the Clara or alveolar cells
lining the airways. In tissue cultures of normal mouse cells, only the
BASCs could grow more of themselves or differentiate into Clara or
alveolar cells. In tissue cultures of the mutant mouse lung cells, the
activated oncogene only triggered growth of the BASCs, not of the more
specialized alveolar cells.
"The stem cells may retain mutations from the same damage that kills
the more specialized cells," Bender Kim speculates. "If the DNA is not
repaired properly, and if the mutation happens to affect a tumor
suppressor gene or oncogene, it could start the process of forming a
tumor. There are certainly suggestions that various tumors might arise
in locations where there has been a previous injury."
The researchers acknowledge that the ultimate stem cell test
remains. "One thing we have not done is taken BASCs and put them back
into the mouse and show in vivo that they perform as stem cells,"
Bender Kim said. "We don't have an assay for that yet."
With hematopoietic stem cells, for example, scientists can inject
the stem cells into the bone marrow of an irradiated mouse and replace
the entire blood system, the basis of bone marrow transplantation.
Solid tissue is trickier. Bender Kim and her colleagues do not yet know
the optimal microenvironment for stem cells of the lung, including the
roles of the neighboring cells that support the stem cells and
specialized lung cells. Still, she says their studies are as rigorous
as the generally accepted reports of stem cells found in the skin,
brain, testes and gut.
The lab has already teamed up with another research group to develop
microscopic fluorescent probes to image the unique molecular surface of
BASCs and track the progress of the naturally arising tumor, Jacks
said. The similar genetic activity profile of mouse tumors with
K-ras mutations to the profile of human lung cancer samples make
the researchers optimistic about the relevance of targeting BASCs for
early tumor detection and chemoprevention in the earliest stage of
disease in people.
Discovery of the lung stem cells could lead to new therapies for
other lung diseases, such as emphysema and cystic fibrosis. “We
tend to emphasize cancer, because we are in a lab that studies
cancer,” Bender Kim said. “Identifying stem cells is the
biggest part of the story. This population could be very useful for
more than cancer.”
In their paper, the researchers envision more medical possibilities,
such as using the adult stem cells to restore defective tissue in
incurable fatal chronic lung diseases, such as alveolar cells that are
destroyed in emphysema. Or scientists could extract the BASCs, alter
their genes, and replace them in a kind of cellular gene therapy for
genetic diseases such a cystic fibrosis.
“This work has identified a new population of cells that links
the normal biology of the lung to lung cancer development,” said
Bender Kim. “We need to continue to improve our understanding of
how normal cells in the body develop, differentiate, and respond to
damage in order to understand the origins of diseases and to develop
better ways to treat them.”
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Jennifer Michalowski
